Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

Abstract Immunotherapy efficacy depends on T cell trafficking to tumors and migrating malignant cells kill them. One barrier homing is the tumor blood vessel wall, which inhibits attachment transmigration through endothelin B receptor, but antagonizing this receptor has not led a clinically approved drug. reason may be hypo‐perfusion, limits area of perfused vessels for attachment. If collapsed can decompressed re‐perfused by alleviating stiffness, then antagonism improve immunotherapy. Here, it tested whether nonselective blocker, bosentan, simultaneously interfering with A induced fibrosis, normalize microenvironment thereby acting as “mechanotherapeutic.” Tumor stiffness monitored ultrasound elastography nanomechanical properties atomic force microscopy find an optimal dose, reprograms cancer‐associated fibroblasts resulting in reduced collagen decompressing vessels. Through mechanism, association increases immunosuppressive hypoxia reduced. Additionally, bosentan CD8 + proliferating fraction. Ultrasound measurements correlate well response immunotherapy, suggesting potential role predictive biomarker immune checkpoint inhibitors.